10-6011411-A-G

Variant names:

• chr10-6011411-A-G
• rs12244380
• NM_000417.3:c.*1461T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000417.3(IL2RA):​c.*1461T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.408 in 152,174 control chromosomes in the GnomAD database, including 13,195 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (13186 hom., cov: 32)
  • Exomes 𝑓: 0.42 (9 hom.)
• Consequence: IL2RA NM_000417.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.638
• Publications: 22 publications found

Genes affected

IL2RA (HGNC:6008): (interleukin 2 receptor subunit alpha) The interleukin 2 (IL2) receptor alpha (IL2RA) and beta (IL2RB) chains, together with the common gamma chain (IL2RG), constitute the high-affinity IL2 receptor. Homodimeric alpha chains (IL2RA) result in low-affinity receptor, while homodimeric beta (IL2RB) chains produce a medium-affinity receptor. Normally an integral-membrane protein, soluble IL2RA has been isolated and determined to result from extracellular proteolyisis. Alternately-spliced IL2RA mRNAs have been isolated, but the significance of each is presently unknown. Mutations in this gene are associated with interleukin 2 receptor alpha deficiency. Patients with severe Coronavirus Disease 2019 (COVID-19), the disease caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have significantly elevated levels of IL2R in their plasma. Similarly, serum IL-2R levels are found to be elevated in patients with different types of carcinomas. Certain IL2RA and IL2RB gene polymorphisms have been associated with lung cancer risk. [provided by RefSeq, Jul 2020]

IL2RA Gene-Disease associations (from GenCC):

• immunodeficiency due to CD25 deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• neonatal diabetes mellitus

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• neonatal diabetes mellitus with congenital hypothyroidism

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• type 1 diabetes mellitus 10

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 10-6011411-A-G is Benign according to our data. Variant chr10-6011411-A-G is described in ClinVar as [Benign]. Clinvar id is 300224.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.439 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL2RA	NM_000417.3	c.*1461T>C		3_prime_UTR_variant	Exon 8 of 8	ENST00000379959.8	NP_000408.1
IL2RA	NM_001308242.2	c.*1461T>C		3_prime_UTR_variant	Exon 7 of 7		NP_001295171.1
IL2RA	NM_001308243.2	c.*1461T>C		3_prime_UTR_variant	Exon 6 of 6		NP_001295172.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL2RA	ENST00000379959.8	c.*1461T>C		3_prime_UTR_variant	Exon 8 of 8	1	NM_000417.3	ENSP00000369293.3
IL2RA	ENST00000649218.1	n.2095T>C		non_coding_transcript_exon_variant	Exon 4 of 4

Frequencies

GnomAD3 genomes AF: 0.408 AC: 61953 AN: 151946 Hom.: 13179 Cov.: 32

Gnomad AFR AF: 0.364

Gnomad AMI AF: 0.275

Gnomad AMR AF: 0.438

Gnomad ASJ AF: 0.419

Gnomad EAS AF: 0.142

Gnomad SAS AF: 0.453

Gnomad FIN AF: 0.465

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.436

Gnomad OTH AF: 0.427

GnomAD4 exome AF: 0.418 AC: 46 AN: 110 Hom.: 9 Cov.: 0 AF XY: 0.424 AC XY: 28 AN XY: 66

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.420 AC: 37 AN: 88

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.500 AC: 1 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.400 AC: 8 AN: 20

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.408 AC: 61997 AN: 152064 Hom.: 13186 Cov.: 32 AF XY: 0.409 AC XY: 30412 AN XY: 74338

African (AFR) AF: 0.363 AC: 15069 AN: 41472

American (AMR) AF: 0.438 AC: 6699 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.419 AC: 1456 AN: 3472

East Asian (EAS) AF: 0.142 AC: 738 AN: 5182

South Asian (SAS) AF: 0.455 AC: 2193 AN: 4818

European-Finnish (FIN) AF: 0.465 AC: 4907 AN: 10544

Middle Eastern (MID) AF: 0.520 AC: 153 AN: 294

European-Non Finnish (NFE) AF: 0.436 AC: 29633 AN: 67972

Other (OTH) AF: 0.426 AC: 898 AN: 2108

Alfa AF: 0.428 Hom.: 30689

Bravo AF: 0.402

Asia WGS AF: 0.307 AC: 1072 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Immunodeficiency due to CD25 deficiency Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.7
DANN	Benign	0.22
PhyloP100		-0.64
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs12244380; hg19: chr10-6053374;